Photodynamic therapy has emerged as a promising tool for inducing immunogenic cell death (ICD), which shows the potential to convert tumor cells into in situ vaccines. However, large amounts of as‐generated tumor‐associated antigens (TAAs) are entrapped in the endo‐lysosomes of tumor‐infiltrating dendritic cells (DCs), resulting in unsatisfactory TAA cross‐presentation and poor or moderate ICD‐associated antitumor responses. Herein, an immune‐enhancing polymer‐reinforced liposome (IERL) with a stable nanostructure and a bioactive surface is developed and it demonstrates its capability to collect TAAs, facilitates TAA endo‐lysosomal escape in DCs, and enhances cross‐presentation of TAAs, which results in the amplification of ICD‐associated antitumor immune responses. By loading photosensitizers, IERLs are able to induce robust antitumor immune responses and immune memory after local irradiation, thereby inhibiting the growth of both primary and distant/metastatic tumors. Additionally, considering the wide applications of liposomal carriers, photosensitizers in IERLs can be easily replaced with photothermal agents and radiosensitizers (or their combinations), which provides a general platform for the rapid development of combined cancer immunotherapy.
Immunogenic cell death (ICD), which in situ generates cancer vaccines and elicits protective cognate anticancer immunity, has brought brightness to cancer immunotherapy. However, poor immunogenicity and low response rate of current ICD‐inducing strategies restrict the development and clinical application of ICD‐based immunotherapy. Herein, a novel calixarene, quaternary ammonium‐modified azocalix[4]arene (CA‐3) that drive bona fide ICD with high efficiency, is presented. In addition, the unique macrocyclic structure offers CA‐3 with great potential to bind with anticancer drugs via host–guest interactions. With these two functions in one molecule, CA‐3 effectively cooperates with various chemotherapeutics to improve their anticancer performance by activating ICD‐associated anti‐tumor immunity. These unique characteristics make CA‐3, a general platform for improving the prognosis of many chemotherapies commonly used in clinical practice. Furthermore, the structure‐activity relationship established in this study also provides insights for the design and synthesis of more efficient calixarene‐based ICD inducers.
Antimicrobial peptides (AMPs) hold great potential for use in tumor treatment. However, developing AMP‐based antitumor therapies is challenging due to circulatory instability, hemolytic toxicity, low selectivity, and poor cell permeability of AMPs. In this study, a polymeric carrier for AMPs (denoted as PAMPm‐co‐PPBEn/PCA) is presented that effectively enhances their anticancer efficacy while minimizing their potential side effects. By integrating multiple responsive structures at the molecular level, the carrier finely controls the spatial distribution of AMPs in different biological microenvironments, thereby effectively modulating their membranolytic ability. Upon employing KLA as the model AMP, the polymeric carrier's hemolytic toxicity during blood circulation is suppressed, its cellular internalization when reaching tumor tissues facilitated, and its membranolytic toxicity toward the mitochondria upon entering cancer cells restored and further enhanced. Animal studies indicate that this approach significantly improves the antitumor efficacy of KLA and reduces its toxicity. Considering that the loading method for most AMPs is identical to that of KLA, the polymeric carrier reported in this study may provide a feasible approach for the development of AMP‐based cancer treatments.
Biological barriers significantly limit the delivery efficiency of drug delivery systems, resulting in undesired therapeutic effects. When designing a delivery system with optimized penetration behavior across the biological barriers, mechanical properties, such as deformability, are emerging as important parameters that need to be considered, although they are usually neglected in current research. Herein, a liquid core nanoparticle (LCN) composed of a polymer‐encapsulated edible oil droplet is demonstrated. Owing to the unique structure in which the liquid oil core is encapsulated by a layer of highly hydrophilic and cross‐linked polymer, the LCN exhibits high mechanical softness, making it deformable under external forces. With high deformability, LCNs can effectively penetrate through several important biological barriers including deep tumor tissue, blood–brain barriers, mucus layers, and bacterial biofilms. Moreover, the potential of the LCN as a drug delivery system is also demonstrated by the loading and release of several clinical drugs. With the capability of penetrating biological barriers and delivering drugs, LCN provides a potential platform for disease treatments, particularly for those suffering from inadequate drug penetration.
The specific recognition of cancer cells by the body's immune system is an essential step in initiating antitumor immunity. However, the decreased expression of major histocompatibility complex class I (MHC-1) and overexpression of programmed death ligand 1 (PD-L1) causes insufficient tumor-associated antigens presentation and inactivation of T cells, which accounts for poor immunogenicity. To remodel tumor immunogenicity, herein, a dual-activatable binary CRISPR nanomedicine (DBCN) that can efficiently deliver a CRISPR system into tumor tissues and specifically control its activation is reported. This DBCN is made of a thioketal-cross-linked polyplex core and an acid-detachable polymer shell, which can maintain stability during blood circulation, while detaching a polymer shell to facilitate the cellular internalization of the CRISPR system after entering tumor tissues and ultimately activating gene editing under exogenous laser irradiation, thereby maximizing the therapeutic benefits and reducing potential safety concerns. With the collaborative application of multiple CRISPR systems, DBCN efficiently corrects both dysregulation of MHC-1 and PD-L1 expression in tumors, thus initiating robust T celldependent antitumor immune responses to inhibit malignant tumor growth, metastasis, and recurrence. Given the increasing abundance of CRISPR toolkits, this research provides an appealing therapeutic strategy and a universal delivery platform to develop more advanced CRISPR-based cancer treatments.
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